Abstract

OBJECTIVE—Dynamically regulated expression of the gap junction protein connexin (Cx)43 plays pivotal roles in wound healing. Cx43 is
normally downregulated and Cx26 upregulated in keratinocytes at the edge of the wound as they adopt a migratory phenotype.
We have examined the dynamics of Cx expression during wound healing in diabetic rats, which is known to be slow.

RESEARCH DESIGN AND METHODS—We induced diabetes with streptozotocin and examined Cx expression and communication in intact and healing skin.

RESULTS—We found that diabetes decreased Cx43 and Cx26 protein and communication in the intact epidermis and increased Cx43 protein
and communication in the intact dermis. Diabetes also altered the dynamic changes of Cxs associated with wound healing. Within
24 h, Cx43 was upregulated in a thickened bulb of keratinocytes at the wound edge (rather than downregulated as in controls,
which formed a thin process of migratory cells). Cx43 decline was delayed until 48 h, when reepithelialization began. Although
Cx26 was upregulated as normal after wounding in diabetic skin, its distribution at the wound edge was abnormal, being more
widespread. Application of Cx43-specific antisense gel to diabetic wounds prevented the abnormal upregulation of Cx43 and
doubled the rate of reepithelialization, which exceeded control levels.

CONCLUSIONS—Cx expression in diabetic skin is abnormal, as is the dynamic response of Cx43 to injury, which may underlie the delayed healing
of diabetic wounds. Preventing the upregulation of Cx43 in diabetic wounds significantly improves the rate of healing and
clearly has potential therapeutic value.

Footnotes

The antisense technology used in this study has been patented by D.L.B. and Colin Green, Department of Ophthalmology, University
of Auckland, Auckland, New Zealand. This technology is being taken into clinical trials by CoDa Therapeutics. D.L.B. owns
stock in CoDa Therapeutics.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.